This proposal is designed to study in detail important substituent and solvent effects on the rates and efficiency of various cyclization reactions, especially Diels-Alder reactions, 1,3-dipolar cycloadditions, ene reactions, and radical cyclizations. In addition, we will develop new methods for the synthesis of the isodityrosine-derived antibiotics (focusing especially on new ways to prepare the key o- aryloxyphenol unit by new cyclization chemistry) and for the antiulcer compound plaunol C and its analogues. In the substituent studies, we plan to determine the reasons behind the very large rate enhancements (up to 105) when the substituents on a carbon a to an oxygen atom are changed from dihydrido to dimethyl. In cases when the substituted carbon is not a to an oxygen atom, the substituent effects are only of the order of 1-10. We will test several reactions and substrates to see whether this abnormally large "gem-diakyl effect" is generally useful for synthesis. In the solvent studies, we win also investigate whether the acceleration of cyclization due to polar solvents that we have seen in Diels-Alder reactions (enhancements of up to 3200 in going from toluene to DMSO) are applicable to other ring systems and cyclizations. The clear demonstration of the synthetic utility of these substituent and solvent effects would be of great value to organic synthesis in general. In the synthetic portion of the proposal, the targets are: the antitumor agent deoxybouvardin, the antifungal antibiotic piperazinomycin, and other members of the isodityrosine-based antibiotics, e.g., K-13; and the antiulcer compound plaunol C and the related ajugarin antifeedants. In all cases, the syntheses are designed so as to be relatively short (7 steps to deoxybouvardin, 8 steps to piperazinomycin, 10 steps to K-13, etc.) and general enough so that many other structurally related systems could be formed quite easily. The principles developed in this proposal e.g., the useful gem-dialkyl effect on cycloadditions and the even more useful polar solvent effect on cycloadditions of compounds whose reactive centers are linked by an ester group, intramolecular cyclizations of alpha-ketosulfonium ion derived from o-(phenylsulfinyl)phenols, reaction of a dihydrotyrosine derivative with an electrophile (e.g., PhSeX) and the phenol of another tyrosine derivative as nucleophile, the use of allenic lactones in cycloadditions, the use of a 3-aryloxycyclohexenone unit with a final deoxygenative aromatization to produce a strained p-cyclophane (e.g., the ring system of piperazinomycin) - would be applicable and of great value to organic synthesis in general. Because of the high intrinsic value of the substituent and solvent studies and the new methods for the synthesis of and the medicinal importance of the targets, the likelihood of an important contribution to health-related science is quite high.